The NINDS Independent Scientist Award will provide the candidate with advanced training in cellular and molecular signaling that will complement his clinical neuroscience training and strong background in cellular and developmental neurobiology. The training will lead to his establishment as an independent investigator, with a special niche at the interface of Neuropathology and Cell Signaling. The University of Virginia, with its internally recognized strength in cell signaling research, is ideal for the proposed project, the long-term goal of which is to elucidate intracellular signaling mechanisms underlying reactive astrocytosis. Reactive astrocytosis is the most prominent cellular response to nervous system injury, which, like the immune response, may have both beneficial and detrimental effects on functional recovery. It would thus be of great importance to understand the signaling pathways activated in astroglial reactions, so that the process can be therapeutically modulated in neurological disorders ranging from spinal cord injury to neurodegenerative diseases. Several parallel and interconnected pathways are likely to regulate astrogliosis; initial work by the candidate has focused on the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway because it represents a common effector of extracellular factors implicated in astrogliosis. ERK/MAPK was found to be highly activated in reactive astrocytes in several human neuropathological states. ERK/MAPK was found to be highly activated in reactive astrocytes in several human neuropathological states. Moreover, transgenic mice which over-express c-most, a specific activator of the ERK/MAPK pathway, exhibited marked reactive astrocytosis and neurologic deficits in comparison to control mice. Preliminary results suggest that ERK/MAPK is constitutively activated in subpopulations of astrocytes in the transgenes in comparison to control mice. The working hypothesis to be tested in this project is that sustained activation of the ERK/MAPK pathway is essential for the induction and maintenance of reactive astrocytic phenotypes. The specific aims address the hypothesis at the systems (aims 1 and 3) and cellular/molecular(aim 2) levels: 1) To test the obligatory role of ERK/MAPK activation in four mouse models representative of distinct forms of transient and persistent astroglial reaction. 2) To test the sufficiency and necessity of ERK/MAPK signaling for astrocyte activation in culture. 3) To generate transgenic mice expressing astrocyte-targeted activators of the ERK/MAPK pathway as critical tests of the working hypothesis.